Avastin (bevacizumab) 100mg vial and carton.
Photo: Courtesy of Genentech
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Study author says the findings aren't a reason to avoid Avastin.

Genentech's blockbuster cancer drug Avastin is linked to a significantly increased risk of blood clots in the veins, said a team of university researchers whose conclusions were quickly challenged by the big biotechnology company.

Wu's study contradicts the conclusions from a pooled analysis of five studies by Genentech researchers, who reported in 2007 that the vein clots did not rise significantly among subjects on Avastin.

Wu said his findings are not a reason to avoid taking Avastin.

"Not in any way," said Wu, a researcher at the Stony Brook University Cancer Center in Stony Brook, N.Y. Rather, the study indicates that patients and their doctors should be watching carefully for symptoms of blood clots, which in severe cases can be fatal, he said in an interview. "For patients, it's important for them to recognize the risk."

Dr. Gary Lyman, a Duke University professor of medicine, said cancer patients in general are at risk for blood clots in veins. Doctors can use blood thinners to reduce the danger that the clots will break off, lodge in the lungs and cause a fatal pulmonary embolism. Signs of a clot include swelling, leg pain and shortness of breath, he said.

Avastin, marketed by Genentech of South San Francisco and the Swiss drugmaker Roche, is designed to block tumor growth by preventing blood vessels from forming to nourish them. Combined with chemotherapy, it can extend the survival of people with certain forms of colon and lung cancer.

But the drug is also associated with serious side effects, including blood clots in the arteries. Other dangers, including hemorrhage and perforations of the bowel, are detailed on the Avastin label approved by the Food and Drug Administration in what is called a "black box warning," the FDA's highest-level alert.

Wu's paper said the risk of blood clots originating in the veins, or venous thromboembolisms, might belong in the black box warning. He said Genentech's review of five studies underestimated the problem.

According to Wu, the 1,745 subjects in Genentech's pooled analysis were too few for the detection of a statistically significant risk. His "meta-analysis," a common approach in medical research, evaluated 7,956 subjects in 15 trials.

The percentage of people developing vein clots was not high in either the Avastin-treated group, where it was about 8.3 percent, or the control group, where it was about 6.1 percent. But by comparing those two numbers, Wu's team found an increase in relative risk with Avastin of 33 percent.

Dr. Philippe Bishop, Genentech's head of clinical development for Avastin, said the results of Wu's analysis might have been skewed by a number of factors, including the different methods of reporting data in each of the 15 trials. But Bishop acknowledged that studies in general have found an incidence of venous clots averaging about two to three percentage points higher among those on Avastin compared with control groups.

Such information is included in Avastin's label, he said. What Bishop disputes is that the data reveal a statistically significant difference in risk of 33 percent. No change in the drug's label is needed, he said.

"I think our label reflects the way Avastin should be used," Bishop said.

Whether Avastin itself is behind the higher incidence of vein clots seen in many studies is still an open question, Wu and Bishop agree. "We don't know if Avastin is the cause," Bishop said. Answering that question would take another very large trial, they agree. Such a trial would be designed to identify other potential causes, such as additional treatments given more frequently to those on Avastin, for example.

Lyman, who helped develop physicians' guidelines for protecting cancer patients from blood clots in the veins, said Wu's paper may make people more aware of the risks. But it may not change medical practice much, he said. "It's just reinforcing what we've suspected," he said.

Doctors must carefully balance a patient's need for effective cancer-fighting drugs against a possibly higher risk of vein clots. They must also carefully consider whether to use blood thinners such as heparin to combat clots, because these drugs can raise the risk of bleeding, he said.

"It's a very complex situation," Lyman said. "It's not always possible to predict what's going to happen in an individual patient."

Genentech shares dropped 20 cents to close at $80.63 before the Wu study was made public. The shares lost another 13 cents in after-hours trading.